11-ketopregnenes and method of producing them



UNITED STATES PATENT OFFICE ll-KETOIPREGNENES AND METHOD OF PRODUCING THEM Lewis H. Sarett, Princeton, N. J assignor to Merck & Con, Ina, Rahway, N. J a corporation of New Jersey No Drawing. Application February 23, 1946,

Serial No. 649,760 i 13 Claims. (o1. 260--397.4)

1 e 2 This invention is concerned generally with In the following description of the invention, novel chemic lc p unds of the cyclopentanodithe stereochemical relationships of substituents methylpolyhydrophenanthrene series and to processes of preparing Same? more particularly 1. A substituent at the (1-3 position which is it relates to novel compounds useful as inter- 5 mediates in the synthesis of the adrenal cortical g g g gi (1-10 methyl group 18 parentheticany hormone A 4,5-3,1l,20-triketo-17(,6), 21-dihyg e are indicated by the following conventions:

droxy pregnene. This application is a continua- A sub stituent at the C47 P tionqmpart of amending application serial No v stereochemical configuration of WhlCh 1s identical 605,194, filed Ju1y'14 19 5, now abandoned with that of the naturally occurring adrenal This hormone is known to occur naturally in hormones, is parenthetically designated (/3); the the adrenal cortex; it has the structural formula: epimeric configuration is designated (a). In the 21 E 03 structural formulae the former configuration is zm'ho shown by writing the 0-17 substituent (hydroxyl) & 3 L to the right of the C-17 carbon side chain, thus 12 1 o=o{ 7\16CH2 CH3 0 l D H, 14 15 onion H CH2 ('JHOH H262, 1o 80f v l A I B i -on o= 3 50 6 7cm 7 (Standard numbering of C-positions) This formula, for purposes of convenience, is

in the latter case above the side chain, thus hereinafter reproduced below in the abbreviated on form: '-0H=0H,

CH3 V CHzOH CH3 0 O 3. The stereochemical relationship of rings A and B is indicated in the formulae by a solid line representing the valence bond in the cis configuration.

40 a In accordance with the present invention it is now found this hormone can be synthesized by reactions indicated as follows: CH3 CH3 H on, CH CH5 0 (tn-coin A 1 l H-GO|H 0 i i o Ho ii'tt R0 H I H II Q MN:

, pH, "1 AIR-+1813! Acyl-halide-fdrnilng reagent 0 H] "HONO 0: to form ozonide, followed by decompositlon [Hydrolysis] CH: CH

XII

lHCI-ECH CH3 CH3 OH 0 --C" :CH

---0 H0 2, catalyst H XIII (H (mix,

H l i a ozenat ng agent H XVI CH3 CH3 CH-CH2X' O \f 1V0 MO R" H XVI C CH3 CH-CHaO R"! O *f n on'or 0 H XIX l Oxidntion 1 Oxidation OH; CH;

OH 0 I CH=CH H XIV lA'cylating agent C 1 OH;

OH O I *-CH=CH5 H XV C CH3 CH-CHzOR" 0 H 1 XVII lHydrolysis CH-CHzOH CH: C H.

CH-CHgO R Hydroxylating agent H Y XXIII Acylating agent Ho u!!! XXIV.

iCHa

amoaa CHI CH-CHQOH Acylating agent CH-CHaOR' XXII l Oxidation C Hg B C H3 CH CH XXIX XXX 1 Hydrolysis CH2OH CH3 In the above formulae, R, R, R", R', R"", R""', and R are acyl; X, X and X" are halogen, and M is an alkali metal or an alkaline earth metal/2.

The reactions above indicated are conducted as follows:

3-hydroxy-11-keto-bisnorcholanic acid (I) is acylated producing 3-acyloxy 11 keto-bisnorcholanic acid (II) which is treated with an agent capable of converting an organic carboxylic acid to the corresponding acid halide, thus forming the acid halide of 3-acy1oxy-11-ket0-bisnorcholanic acid (III). Upon treatment of this acid halide with an alkali metal azide or alkaline earth metal azide, the azide of 3-acylo-xy-1lketobisnorcholam'c acid (IV) is formed. Decomposition of this azide with an acidic aqueous soluticn produces 3-acyloxy-11-keto-20-aminopregnane (V).

Upon treatment of this compound (V) with nitrous acid, a mixture containing predominantly A1120 3 acyloxy ll-keto pregnene (VI) and A -3-acy1oxy-1l-keto-pregnene (VII) and a minor amount of B-acyloxy-l1keto-20-hydroxypregnane (VIII) results. The proportion of the desired compound (VI) present in this mixture can be increased by treating the mixture with an aromatic sulfonyl halide followed by further treatment with a base to cause removal of the elements of the corresponding aromatic sulfonic acid. The mixture of these compounds (VI) and (VII) or of (VI), (VII) and (VIII), is then treated with ozone followed by decomposition of the ozonide, producing 3-acyloxy-1l,17-diketoetiocholane (IX) and 3-acyloxy-11-keto-1'7- formyletiocholane (X). Compound (X) is oxidized to 3-acyloxy-ll-ketoetiocholanic acid (XI) which is separated from compound (IX) by extraction with alkali. Compound '(IX) is hydrolyzed to form 3-hydroxy-11,17-diketoetiocholane (XII) which is treated with acetylene to form 3,17 dihydroxy 11 keto-pregnine (XIII). This compound (XIII) is catalytically hydrogenated to produce A -3,1'7-dihydroxy- 11-ketopregnene (XIV) which is acylated to form fil -3 acyloxy 17 hydroxy-ll-ketopregnene (XV), and this compound is halogenated to pro-- duce A -3-acyloxy 11 keto-21-halopregnene (XVI). When treated with an alkali metal salt or alkaline earth metal salt of an organic acid, this compound yields A -3,21-diacyloxy-11- ketopregnene (XVII) which is hydrolyzed producing A -3,21 dihydroxy 11 ketopregnene (XVIII). The latter product (XVIII) is' partially esterified and the mono ester (XIX) thus produced is oxidized to convert the unesterified hydroxy group in the 3 position to a keto growl thereby yielding the ester A -3,11-diketo-21- acyloxy-pregnene (XX). This product (XX) is hydrolyzed and the A ,11-diketo-21-hydroxypregnene (XXI) thus formed is acylatedproducing N -3,11-diketo-2l-acyloxypregnene (XXII). I-Iydroxylation at the unsaturation of the last mentioned compound (XXII) results in the production of 3,l1-diketo-17(;i),20,21-trihydroxypregnene (XXIII) which is then acylated to form 3,11-diketo-17 ([3) -hydroxy-20,21-diacyloxypregnene (XXIV). When brominated, this compound yields 3,11-diketo-4-bromo-l'7 (/3) -hy-- ventional operations, for example chromatography, and compound (XXIX) hydrolyzed to produce the desired adrenalhormone, A -3,11,20- triketo- 17 (B) ,ZI-dihydroxypregnene.

The present invention is concerned with com-" pounds having basic structural formulae of the type illustrated by. intermediates VI through 111 XII above, i. e., compounds represented by the formula:

CH3 CH1 wherein R is hydrogen or an acyl group, and R is a radical of the group consisting of alkylidene, groups readily convertible to alkylidene by removal of H20, and keto, particularly such compounds wherein R is one of the radicals represented by the formula:

=CHCH3, CH=CH2, --CHOHCH3 and =0 ZQ-hydroxypregnane, is obtained. Although the reagent presently preferred for use in this treatmentis nitrous acid which if desired can benformed. in situ, oxides of nitrogen thatyield nitrous; acid whenlin contact with water can lie-substituted therefor. Ithaslbeenfound, pursuant, tothis invention, that formation of the; desired unsaturatedproducts in preference to the hydroxy compound can be favorably influenced by conducting the reaction in pyridinewhich, for: thispurpose, is the preferred solvent me ium, although alcohol water or aceticacid may: bemsed-with less satisfactory results,

V ketopregnene, A2031 -.3-acyloxy-Ileketopregnene and 3+acyloxy-11-keto-20-hydroxypregnane ob-- tained'asabove describedlis next treatedwith a reagent which, in. reactin with the 3,-acyloxy lir-keto-20l-hydro-xypregnanecomponent of: the mixture, produces; the: effect of? increasingv therelative proportionof unsaturated :components inthee mixture while decreasing or'substantially wholly, removing the hydroxy' componentv Of -this.; classof reagents, which can bBxCOl'lVGl'liGIltlY' defined; as. those capable of converting a hydroxyl containing. alkyl substituent'v t0. alkylidene b'yrremoval of H20, the reagentrpresently preferred is an aromatic sulfonyl halide employed inconjunction with a base suchas hydrazine, alkali metalhydroxides andialkoxides; alkalineearth hydroxides. alkoxides, or tertiary: amines,-.

specifically p-toluenesulfonyl chloride and collidine or pyridinel As a result oft-this treatment, a, mixture of A' -3-acyloxy-1l-ketopregnene and;;.A -3+acyloxy-l1-ketopregnene'is obtainedthatais-,- used in the next step without being sepa.- ratedinto its components;

The next step in'the process according. to=thisr inventionis treatment of this lastxdescribed mixture of unsaturated.'products with:ozone, prefe erablys'while such products are dissolved 111L211:

presently preferred solvent.

12 organic solvent, whereby a mixture of ozonides is obtained that upon decomposition yields 3- acyloxy-11-keto-l'7-fcrrnyletiocholane and 3-acyloxy-l1,1'7-diketoetiocholane. Among the solvents useful for this operation are the lower'aliphatic alcohols simple low-molecular-weight esters and the like, including mixtures thereof; a mixture of methanol andethylaceta'te is the The ozone used in this reaction is obtained by conventional operations i. e. high potential electrical discharge in an oxygen atmosphere, and the ozone containing oxygen is bubbled through the solution of the, unsaturated compounds in the. organic, solvent to yield the desired ozonides. Decomposition of the ozonides to produce the 17-formyl and 17-keto etiocholane compounds above mentioned is effected by adding a mild reducingagent, e. g. preferably zinc dust and acetic acid, to the ozonide mixture, warmingitgently and then removing unreacted reducing agent; Thei mixture of decomposition products thus obtained then is treated with an oxidizing agent-suchas-potassium permanganate (which is preferred for this purpose), chromic acid or the like, whereby the 3- acyloxy-11-keto-17-formy1 etiocholane' component of the mixture is converted to 3-acyloxy 11- ketoetioch-olanic acid While the 3-acyloxy-1Ll7- diketoetiocholane remains unaffected. Theacid component of this mixture may be separated by alkali treatment and converted to certain usefull products suchas: dehydrocorticosterone.or; ifde sired: it can: be converted to 3 -acyloxy-'11,1!7- di'-: ketoetiocholane. 7

The" conversion of 3-acyloxy lleketoetiocholanic acid to 3-acyloxy-1l,l7-diketoetio'cholane maybe efiectedasfollows: the above-mentioned acid? starting material? may be. converted t'o the' corresponding carboxyhalo compound by? treat ment with a reagent; capable. of converting: a CO2Hgroup to a CO (halogen), e; .g. a thio'ny-l halide, and this carboxyhalo'compound maytherr be treated-with an;azide,- e; g. sodium-=azide';.fol'- lowed'by decomposition preferably by. heating with. adilute" aqueous acid; whereby 3-acyloxye- 'llekleto l'7 aminoetiocholane; may: be; obtained:

By-treating' this compound with a; hypohaloust acid: followed" by" heating at 253400 C: with; anorganic base such as pyridine or collidinaand;

; then-hydrolyzing, the product with azdiluteracid,

3-acy1oxy 11,17 diketoetiocholane may b63013? tained;

The, 3-acyloxy-l,-1-,17-- diketoetiocholanei': pro.-: duced :as: hereinbefore described: is next: treated with an alkali under; saponificati'oni conditions; e. g. refluxing with;aloweraliphatic alcohol soe lution; of an alkali metal hydroxide; Wherebyl 3hydrOXy:-11,17rdikQtO8tiOGhO13d'l9 obtained:, If desired .thisllast-mentioned compoundcambe; treatedv with an oxidizing agent, .preferablyp chromium trioxide in dilute acetic acid,- to pro ducex.3,11,17-triketoetiocholane (lVL P. l34-135. 0.).

The: following example .of the prac-ticemf the: instant: invention issprovided by way of illustra tion; not of limitation.

Examplenl -3 a'c'etoxyeiiJcetopregnene (VI), A 3-acetoxy-1l lcetoprcgnene- (VI I and' 3-uc etomy 11ilceto-20 hydr0xypregnane: (V-II I .-'-Ihestart ing materialused in the operations nowvto be described; i.- er, 31o) -acetoxy-11-keto'-20-aminopregnane; may be-obtained by 1 the reactions do scribed .in .1 general terms r above and disclosed l pyridine and dilution of the residue with water,

extraction with ether yielded an ether solution which, after washing with water, hydrochloric acid (0.5 N.) and more water, was. reduced to dryness in vacuo to yield a residue. This residue contained, in addition to the desired A 3(a) -acetoxy ll ketopregnene, certain other compounds including fi -3(a) acetoxy 11- ketopregnene, 3 (a) -acetoxy-11-keto-20-hydroxypregnane, unreacted 3(a) -acetoxy 11 keto-29- aminopregnane and the corresponding hydrolysis products, i. e., A -3(a)-hydroxy-ll-ketopreg nene, M -3 (a) -hydroXy-11-ketopregnene, 3 (a) hydroxy-ll-keto-20-hydroxypregnane and 3(a)- hydroxy 11 keto 20 aminopregnane. This mixed product was obtained as an oil.

The oil so obtained was dissolved in 5.5 cc. of pyridine, 3.3 grams of p-toluene sulfonyl chloride were added, and the solution left at room temperature for 62 hours. Water and ether were again added until layer separation took place, the ether layer was separated, washed with dilute acid, alkali and water, and evaporated to dry ness. The oil thus recovered was then refluxed with collidine for one-half hour. The solution was cooled, dissolved in ether, washed with dilute hydrochloric acid and water, then concentrated to dryness on a steam bath.

The mixture of unsaturates so obtained was dissolved in equal parts of ethyl acetate and methanol and then treated with twice the theoretical quantity of ozone at 78 C. The solution Was then treated with zinc dust and acetic acid, warmed to room temperature; decanted, and concentrated in vacuo. The residue was dissolved in ether, washed with Water and dilute extract, filtration and crystallization from dilute acetone gave 3(a)-acetoxy-1l-ketoetiocholanic acid. The neutral fraction from the extraction was concentrated, treated with Girards reagent T, and there was obtained about 30% yield of 3 (a) -acetoxy-11,17-diketoetiocholane.

Refiuxing with l-N-methanolic potassium hydroxide gave the corresponding hydroxy diketone, melting point 187-138 C. and having the formula:

CH C 3 14 While the above example i is limited to the B-acetoxy compound, ,it willbe understood that compounds having, instead of the acetyl group, other acyl radicals, sueh'as those derived from propionic, butyric, Valerie, caproic, capric, benzoic, toluic acids, come within the scope of the invention, the particular acid used being dictated chiefly by matters of convenience and cost.

Thus the invention includes the intermediates having the structural formula:

om 0H3 where R is a member of the group consisting of acyl and H. I

While in the example the starting material used had the hydroxy group in the 3 position in the trans form, a compound having this group in the cis form may be used as the steric con figuration of the hydroxy group in the 3 position ucts which results from operation at such tem-.

peratures.

Unless otherwise stated, the reagents can be used in difierent proportions than are indicated in the above example; the proportions unless otherwise indicated, are not critical provided enough of the reagents is employed to assure sub-1 stantially complete reaction to produce the desired products. v

All melting points in this specification are corrected.

The compounds above described having the basic structural formula:

pound) and this starting material is oxidized,

pi? "915W- chi of the formula-i By thus oxidizing 3(al -hydroxy-11,17diketoetiocholane, 3,1*1,l7;tri ketoetiocholane (M. P. 134135 C.) is obt'a'inedl Since certain changes in carrying out the above process, and certain modifications in the intermediates which mloody the invention may be made without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted in an illustrative and not in a limiting se r What is claiined is: i V 1. -3a-acetoxy-11--ketopregnene. 2 Th process. that comprises (d) treating a "-1r-iietoammnworgiisne with n1"- a' cl to produce a' rftibn i'nixture mg a 3' ac cx 1'I-keto 2o-hydrcxy'- fire gnune; a A -fl-acyloxy -H ketopregnene" r and a A2031 3- acyloxy 11 ketopreg'riene;

(or treating this resultant first reaction mixture aromatic s 'iil'foriyl ns-11 1s; and then r 11 in? t ix-ture' with ar'rorganic base there b5? removing the elements of" the aromatic sulfofiiciaicid aii'd producing a: second reaction: mixture containing predominantly A -3-acyloxy- I-I-ketcipre'gnene and" A '-3 -acyloxy-'1I-ketm pregnene; (c) treating thissecond reaction mix ture with ozone to form corresponding ozonides and then decomposing the ozonides to produce 9; thi rd reaction -mixture of 3-acyloxy-1 l:, 1" (-dike toetiocholane and 3-acyloxy-ll-keto-l'l formyl-r t'" "planet ((2) oxidizing" this" third reaction *5 to convert the rarmyi compound t'o'f 3- kfeto'e ochloi'ia'nic acid;' (of) extract ingsaid acid" from the reaction mixture; and (1') treating said 3-acyloxy-1LI'T diKetoetiochOIane with ailiali under sap'on'ificatiorr conditions' to produce 3-hydroxy-11,17-dilxetoetlocholane, said aeyioey g'i6ups h'iiig derived from lowei aliphatic acids.

3. The process that comprises heating 3-acet- OXy 11 keto ZO -"aminQpregnane with nitrous acid to produce a first reaction mixture containing 3 acetoxy l1 kQto-ZO-hydroxypregnane, A 7 -3-acetoxy-l'l ketopregnene and A 3- acetoxy-ll-ketopregnene, treating this first reaction mixture with an aromatic sulfonyl halide and then refluxing the mixture with 'an organic base thereby removing'the elements of the arcmatic sulfonic acid and producing a second reaction mixture containing predominantly A 3-acetoxy-11-ketopregnene and A -3-acetoxyll-ketopregnene; treating this second reaction unit-tare witli ozone t6- forfii the corresponding decomposing messo'z'onide's' reaction mixture or s-acct o ,l'l dili'e'toetiocl'iolaii and 3=acetox '-i'r- Reta-'17 formyietiocholm1 oxidizing this thirdreaction mixture to convert the f'orm yl' com: pound 7 to"- 3-1acetoxy-1 L-ketoetiocholanic. acid;

extracting the said acid from the reaction mixacid in the presence of pyridine t6 protlu of the" aroma 16 sulzioniciac d second reaction nxture containing predomi- QQ P9i F1 I z9 9n and than 999 s1 a these-ozonid'es to produce a-third reaction r-njixturge of 3acetoxy-l-1','l7-diketoetiocho1ane and B-acet; oxy-l l keto-l l-formyletiocholane;; oxidizing. this third; reaction mixture to convert the formylcomf' pound to 3-acetoxy-ll-ketoetiocholanic acid; tracting the said acid from the reaction mixture with alkali; and recovering 3--acetoxy 11-717 -"dike--" toetiocholane'. V I

5. The processthat comprises reacting 3*-'a'cyl oxy-ll-ketoaminopregnane with nitrous acid treatingthe reaction mixturethuS produced witir aromatic sulfonyl halide aind then w H a teitia'ry amine; oxidizing the resulting p'ro cessively with ozone and-apermanganat covering 3-acyloxy-1117-diketoetiooholarfe' s' d a'cyloxy groups being derived from lower aliphatic acids. 6; process'tha t comprises reacting" e-a c c'xy-l 1-ketd aminopregnane with" nitror treating the reaction r'rfixture with an are sulfoi'iy l halid andth nwitli collidine; 0 di the resulting mixture successivelyw apermanganate; and rec overin'g' seesaw- 1 diketoetiochola'iie' saidacy loxy groups being de rived from lower aliphatic acidi g 7. The process: that comp iss reacting a acyloxy-11-keto=20=aininbpregnane with nitrous acid to produoeacompound of the class consist? ing I of A f -I'B- acyIQxY-I1 ketoprgnehes m fi-ac'yloxy-l keto'prgn'enes" saidi acy groups h'eing 'd'eriveid from lower'aliphatic"acids 8; Theprpcess that comprises reacting a 3?; acyloxy -lI-keto ZO aminopregnane with a M 3-acy1bxy1i'-keto regpene said as 9 groups being derived from lower aliphaticja 9. The'processthat comprises ractin '3'-ace -"f' ox'y-l I-l tetd-ZO aminopregnanje with nitrous adid to" produce A2 2 =3Facetoxy II-ketopregrinei 1Q. I he process that comprises reacting a 3" acylbx y}l-l ketoqq liydroxypregnane was" an aromatic'sulfonyl halidejand liating there ploduct'with a b ase tdfo'im'thecorrespondih I acyloxy-ll-ketopregnene said acyloxy groupwa ing derived from lower aliphatic acids.

11. The processthat comprises reacting 3-acetoxy-ll-keto-20-hydroxyprgnane with an aromatic sulfonyl halide and heating the reaction product with a base to form the corresponding 3- acetoxy-ll-ketopregnenel 12. In the synthesis of 3-acetoxy-11,17-dil etoetiocholane, the steps that comprise reacting 3- acetoxy-ll-keto-20-hydroxypregnene with an 7 a-aromatic sulfonyl halide; treating the reaction REFERENCES ormn The following references are of record in the file of this patent:

and 991 18 UNITED STATES PA'I'ENTS Name Date Schoeller Sept. 28, 1937 Hildebrandt Dec. 26, 1939 Marker Dec. 31, 1940 Bockmuhl Sept. 2, 1941 OTHER REFERENCES Reichstein: Helv. Chim. Acta, 20, pp. 978, 982

(1937). Ruzicka: Helv. Chim. Acta, 25, 1297-4305 (1942).

Euw: Helv. Chim. Acta, 25, pp. 990, 998 and 1010 (1942) 2 ibid., 27, PP. 822 and 832 (1944).

Number 

1. $17,20-3A-ACETOXY-11-KETOPREGNENE. 